Imidazole with angiotensin II antagonist properties

ABSTRACT

This invention relates to novel substituted imidazole and triazole derivatives which antagonize the binding of angiotensin II to its receptors. The compounds are useful in the treatment of hypertension, heart failure, glaucoma, and hyperaldosteronism. Methods of making the compounds, novel intermediates useful in the preparation of the compounds, pharmaceutical compositions containing the compounds, and methods of using them are also covered.

This is a continuation-in-part of U.S. Ser. No. 07/984,594, filed Dec.2, 1992, now abandoned; which is a continuation-in-part of U.S. Ser. No.07/802,652, filed Dec. 5, 1991, now abandoned.

BACKGROUND OF THE INVENTION

The instant invention relates to novel imidazole and 1,2,4-triazolederivatives which antagonize the binding of angiotensin II (AII) tocellular receptors. This AII antagonist property renders these compoundsuseful for treatment of angiotensin-related hypertension.

The enzyme renin acts on a blood plasma α₂ -globulin, angiotensinogen,to produce angiotensin I, which is then converted byangiotensin-converting enzyme to AII. The latter substance is a powerfulvasopressor agent which has been implicated as a causative agent forproducing high blood pressure in various mammals, such as rats, dogs,and humans. The compounds of this invention inhibit the action of AII atits receptors on target cells and thus prevent the increase in bloodpressure produced by this hormone-receptor interaction. By administeringa compound of the instant invention to a species of mammal withhypertension due to AII, the blood pressure is reduced. The compounds ofthe invention are also useful for the treatment of congestive heartfailure, hyperaldosteronism and glaucoma.

European Application Number 253,310 (U.S. Pat. No. 5,138,069) disclosesimidazoles of the formula ##STR1##

The compounds are disclosed as having utility in treating hypertensionand congestive heart failure.

European Application Number 323,841 discloses substituted pyrrole-,pyrazole-, and triazole-containing compounds of the formulas ##STR2##

European Application Number 324,37 (U.S. Pat. Nos. 5,128,355 and5,138,069) discloses a pharmaceutical composition of a diuretic or anonsteroidal antiinflammatory drug useful for blocking the angiotensinII receptor.

U.S. Pat. No. 4,355,040 discloses imidazole-5-acetic acid derivatives ofthe formula ##STR3## wherein R¹ is lower alkyl, cycloalkyl or, phenylwhich may be substituted with one to three of halogen, nitro, amino,mono(lower alkyl)amino, di(lower alkyl)amino, lower alkyl, loweralkoxyl, benzyloxyl or/and hydroxyl; X¹, X², and X³ are each hydrogen,halogen, nitro, amino, lower alkyl, lower alkoxyl, benzyloxyl orhydroxyl; Y is halogen and R² is hydrogen or lower alkyl; provided thatX¹ is halogen, lower alkyl, lower alkoxyl, benzyloxyl or hydroxyl whenR¹ is unsubstituted or substituted phenyl only with one halogen,di(lower alkyl)amino, lower alkyl or lower alkoxyl, and its salts. Thecompounds are disclosed as having antihypertensive activity.

European Applications Numbers 403158 and 403159 disclose angiotensin IIreceptor antagonists of formula ##STR4## wherein R¹ is phenyl, biphenyl,naphthyl, or adamantylmethyl, which are unsubstituted or substituted byone to three substituents selected from Cl, Br, F, I, C₁ -C₄ -alkyl,nitro, CO₂ R⁷, tetrazol-5-yl, C₁ -C₄ -alkoxy, hydroxy, SC₁ -C₄ alkyl,SO₂ NHR⁷, SO₃ H, CONR⁷ R⁷, CN, SO₂ C₁ -C₄ alkyl, or C_(n) F_(2n1),wherein n is 1 to 3;

R² is C₂ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₃ -C₆cycloalkyl, , or (CH₂)₀₋₃ phenyl unsubstituted or substituted by one tothree substituents selected from C₁ -C₄ alkyl, nitro, Cl, Br, F, I,hydroxy, C₁ -C₄ alkoxy, or NR⁷ R⁷ ;

X is a single bond, S, or O:

R³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, COOR⁷, CONR⁷ R⁷, NO₂,or C_(n) F_(2n1), wherein n is 1 to 3;

R⁴ and R⁵ are independently hydrogen, C₁ -C₅ alkyl, phenyl-Y-,naphthyl-Y-, or biphenyl-Y-, wherein the aryl groups are unsubstitutedor substituted by one to three substituents selected from Cl, Br, F, I,C₁ -C₄ alkoxy, hydroxy, CO₂ R⁷, CN, NO₂, tetrazol-5-yl, SO₃ H, CF₃,CONR⁷ R⁷, SO₂ NHR⁷, C₁ -C₄ -alkyl, or NR⁷ R⁷, or by methylenedioxy,phenoxy, or phenyl, except that R⁴ and R⁵ are not both selected fromhydrogen or C₁ -C₆ -alkyl;

Y is a single bond, O, S, or C₁ -C₆ alkyl which is straight or branchedor optionally substituted by phenyl or benzyl, wherein each of the arylgroups is unsubstituted or substituted by halo, NO₂, CF₃, C₁ -C₄ alkyl,C₁ -C₄ alkoxy, CN, or CO₂ R⁷ ;

R⁶ is --Z--COOR⁶ or --Z--CONR⁷ R⁷ ;

Z is a single bond, vinyl, CH₂ --O--CH₂ --, methylene optionallysubstituted by C₁ -C₄ alkyl, one or two benzyl groups, thienylmethyl, orfurylmethyl, or --C(O)NHCHR⁹ --, wherein R⁹ is H, C₁ -C₄ alkyl, phenyl,benzyl, thienylmethyl, or furylmethyl;

each R⁷ independently is hydrogen, C₁ -C₄ alkyl, or (CH₂)_(m) phenyl,wherein m is 0 to 4; and

R⁶ is hydrogen, C₁ -C₆ alkyl, or 2-di(C₁ -C₄ alkyl)amino-2-oxoethyl; or

R⁵ and R⁶ are both hydrogen, R⁴ is and --Z--COOR⁸ and Z is other than asingle bond; or a pharmaceutically acceptable salt thereof.

Copending U.S. application Ser. No. 07/757021 covers novel anilidederivatives which antagonize the binding of angiotensin II to itsreceptors. The compounds are those of formula ##STR5##

SUMMARY

The instant invention concerns a compound of formula ##STR6## or thepharmaceutically acceptable acid addition or basic salts thereof whereinX, B', R, R₁, R₂, R₃, R₄, R₅, and R₆ are as defined below.

Angiotensin II mediates a variety of responses in various tissues,including contraction of vascular smooth muscle, excretions of salt andwater from kidney, release of prolactin from pituitary, stimulation ofaldosterone secretion from adrenal gland, and possible regulation ofcell growth in both cardiac and vascular tissue. As antagonists ofangiotensin II, the compounds of Formula I are useful in controllinghypertension, hyperaldosteronism, and congestive heart failure inmammals. Additionally, antihypertensive agents as a class have beenshown to be useful in lowering intraocular pressure. Thus, the compoundsof Formula I are also useful in controlling glaucoma.

The invention also includes a pharmaceutical composition comprising anantihypertensive effective amount of a compound of Formula I above inadmixture with a pharmaceutically acceptable carrier or excipient and amethod for treating hypertension in a mammal suffering therefrom whichcomprises administering to said mammal the above pharmaceuticalcomposition in unit dosage form.

Further, the invention includes a pharmaceutical composition comprisingan amount of a compound of Formula I above effective for treatinghyperaldosteronism in admixture with a pharmaceutically acceptablecarrier or excipient, and a method for treating hyperaldosteronism in amammal suffering therefrom comprising administering to said patient theabove pharmaceutical composition in unit dosage form.

Also, the invention includes a pharmaceutical composition comprising anamount effective for treating congestive heart failure of a compound ofFormula I above in admixture with a pharmaceutically acceptable carrieror excipient and a method of treating congestive heart failure in apatient suffering therefrom comprising administering to said patient theabove pharmaceutical composition in unit dosage form.

Also the invention includes a pharmaceutical composition comprising anamount of a compound of Formula I above effective for treating glaucomain admixture with a pharmaceutically acceptable carrier or excipient;and a method of treating glaucoma in a patient suffering therefromcomprising administering to said patient the above pharmaceuticalcomposition in unit dosage form.

The instant invention further includes methods for making compounds ofFormula I.

DETAILED DESCRIPTION

The compounds of the present invention are represented by the formula##STR7## or a pharmaceutically acceptable salt thereof wherein R₁ is

adamantylmethyl,

phenyl,

biphenyl, or

naphthyl, each of which is unsubstituted or substituted by one to threesubstituents selected from

Cl,

Br,

F,

I,

alkyl of from one to four carbon atoms,

nitro,

tetrazol-5-yl,

alkoxy of from one to four carbon atoms,

hydroxy,

SO₃ H,

SO₂ alkyl of from one to four carbon atoms,

CN,

C_(n) F_(2n+1) wherein n is an integer of from 1 to 3,

CO₂ R₄,

SO₂ NHR₄,

NHSO₂ R₄,

NHSO₂ C_(n) F_(2n+1),

CON(R₄)₂ wherein R₄ is hydrogen or lower alkyl;

X is a single bond, S, or O;

R₂ is

alkyl of from two to ten carbon atoms,

alkenyl of from two to ten carbon atoms,

alkynyl of from three to ten carbon atoms,

cycloalkyl of from three to six carbon atoms,

(CH₂)_(m) phenyl wherein m is an integer of from zero to eight andphenyl is unsubstituted or substituted by one to three substituentsselected from alkyl of from one to four carbon atoms,

nitro,

Cl,

Br,

F,

I,

hydroxy,

alkoxy of from one to four carbon atoms, or NR₄ R₄ wherein R₄ is asdefined above;

R₃ is

hydrogen,

Cl,

Br,

F,

I,

CHO,

hydroxymethyl,

alkyl,

aryl,

heteroaryl,

CO₂ R₄,

CONR₄ R₄,

NO₂, or

C_(n) F_(2n+1) wherein n is as defined above;

R₄ is hydrogen or alkyl of from one to five carbon atoms,

R is hydrogen or alkyl of from one to five carbon atoms which alkyl isunsubstituted or substituted with

CN,

CO₂ R₄,

tetrazol-5-yl,

CONHR₄,

CONH(CH₂)_(n) CO₂ R₄

phenyl unsubstituted or substituted by one to three substituentsselected from

alkyl of from one to four carbon atoms,

nitro,

Cl,

F,

I,

hydroxy,

alkoxy of from one to four carbon atoms, or NR₄ R₄ wherein R₄ is asdefined above;

Additionally R is

OR₄,

O(CH₂)_(n) CO₂ R₄.

R₅ and R₆ are each independently

hydrogen,

halogen,

alkyl of from one to five carbon atoms,

alkyloxy of from one to five carbon atoms,

NO₂,

NHCOR₄,

NHSO₂ R₄,

(CH₂)_(n) CO₂ R₇ wherein n and R₄ are as defined above: and

B' a bond, or CO; and

the indicates a double or single bond.

More preferred compounds of the invention are those of Formula I wherein

R₁ is

phenyl

biphenyl, or

naphthyl, each of which is unsubstituted or substituted by one to threesubstituents selected from

Cl,

F,

alkyl of from one to four carbon atoms,

nitro,

tetrazol-5-yl,

alkoxy of from one to four carbon atoms,

hydroxy,

SO₃ H,

CN,

C_(n) F_(2n+1) wherein n is an integer of from 1 to 3,

CO₂ R₄,

SO₂ NHR₄,

NHSO₂ R₄,

CONR₄ R₄ wherein R₄ is hydrogen or lower alkyl;

X is a single bond or S;

R₂ is alkyl of from two to eight carbon atoms, or cycloalkyl of fromthree to six carbon atoms,

R₃ is

hydrogen,

Cl,

F,

I,

CHO,

hydroxymethyl,

alkyl,

aryl,

pyrrole,

CO₂ R₄,

CONR₄ R₄,

NO₂, or

C_(n) F_(2n+1) wherein n is as defined above;

R₄ is hydrogen or alkyl of from one to four carbon atoms,

R is hydrogen or alkyl of from one to four carbon atoms unsubstituted orsubstituted with

CO₂ R₄,

tetrazol-5-yl,

CONHR₄ wherein R₄ is as defined above;

R₅ and R₆ are each independently

hydrogen,

alkyl of from one to four carbon atoms,

alkyloxy of from one to four carbon atoms,

NO₂,

NHCOR₄,

NHSO₂ R₄,

(CH₂)_(n) CO₂ R₄ wherein n, R₄, is as defined above; and

B' is a bond, or CO.

The indicates a double bond.

Still more preferred compounds of the invention of Formula I wherein

R₁ is phenyl substituted by one to three substituents selected from

Cl,

F,

trifluoromethyl,

nitro,

methyl,

methoxy,

hydroxy,

sulfonamido,

carboxy,

carboC₁ -C₄ alkoxy,

carbamoyl,

CN, or

tetrazol-5-yl;

X is a single bond;

R₂ is alkyl of from two to eight carbon atoms;

R₃ is hydrogen,

R₄ is hydrogen,

R is CH₂ CO₂ R₄ is hydrogen or lower alkyl;

R₅ is alkyl of from to four carbon atoms;

R₆ is hydrogen; and

B' is a bond.

The indicates a double bond.

Most especially preferred compounds of the invention are:

Ethyl4-[[2-butyl-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate;

Methyl4-[[2-butyl-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]-3-chlorobenzoate;

Methyl4-[[2-butyl-5-[(1,2-dihydro-5-methyl-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate;

Ethyl4-[[2-butyl-4-chloro-5-[(1,2-dihydro-6-methyl-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate;

Methyl 4-[[2-propyl-5-[(1,2-dihydro-1-methyl-2-oxo-3Hindol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate;

Methyl4-[[2-butyl-5-[(1,2-dihydro-4-methyl-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate;

Methyl4-[[2-butyl-5-[(1,2-dihydro-7-methyl-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate;

Methyl4-[[2-butyl-5-[(5-chloro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate;

Methyl4-[[2-butyl-5-[(1,2-dihydro-7-methoxy-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate;

Ethyl3-[[2-butyl-1-[[4-(methoxycarbonyl)phenyl]methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-5-carboxylate;

Ethyl4-[[2-butyl-4-chloro-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate;

Ethyl3-[[2-butyl-1-[[(4-methoxycarbonyl)phenyl]methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-1-acetate;

(E)-4-[[2-butyl-4-chloro-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoicacid;

4-[[2-butyl-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1yl]methyl]benzoicacid;

4-[[2-butyl-5-[(1,2-dihydro-7-methoxy-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoicacid;

3-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-1-aceticacid;

3-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-5-carboxylicacid;

4-[[2-butyl-5-[(1,2-dihydro-5-methyl-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]-benzoicacid;

3-[[2-butyl-1-[[2'-carboxy-[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-1-aceticacid;

4-[[2-butyl-5[(1,2-dihydro-1-methyl-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoicacid;

4-[[5-[[1-(aminocarbonyl)-1,2-dihydro-2-oxo-3H-indol-3-ylidene]methyl]-2-butyl-1H-imidazol-1-yl]methyl]benzoicacid;

Methyl4-[[(2-propyl-5-[1,2-dihydro-1-(methylaminocarbonyl)-2-oxo-3H-indol-3-ylidene]methyl]-1H-imidazol-1-yl]methylbenzoate;

Methyl4-[[2-butyl-5-[1,2-dihydro-1-hydroxy-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate;

Ethyl(Z)-(±)-2,3-dihydro-3-[[3-[[4-(methoxycarbonyl)phenyl]methyl]-2-propyl-3H-imidazol-4-yl]methylene]-4-methyl-2-oxo-α-propyl-1H-indole-1-acetate;

3-[[2-butyl-3-[[4-(1H-tetrazol-5-yl)-phenyl]methyl]-3H-imidazol-4-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-1-aceticacid;

Methyl(Z)-2,3-dihydro-3-[[3-[[4-(methoxycarbonyl)phenyl]methyl]-2-propyl-3H-imidazol-4-yl]methylene]-4-methyl-2-oxo-1H-indole-1-acetate;

4-[[2-butyl-5-[(1-butyl-1,2-dihydro-2-oxo-3H-indol-3-ylidenyl)methyl]-1H-imidazol-1-yl]methyl]-3-chlorobenzoicacid;

4-[[2-butyl-5-[(1,2-dihydro-7-methyl-2-oxo-3H-indol-3-ylidenyl)methyl]-1H-imidazol-1-yl]methyl]benzoicacid;

4-[[5-[(1,2-dihydro-2-oxo-1-propyl-3H-indol-3-ylidenyl)methyl]-2-propyl-1H-imidazol-1yl]methyl]benzoicacid;

(E)-4-[[5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidenyl)methyl]-2-propyl-4-(1H-pyrrol-1yl)-1H-imidazol-1-yl]methyl]benzoicacid;

Ethyl(Z)-3-[[2-butyl-3-[[4-(methoxycarbonyl)phenyl]methyl]-3H-imidazol-4-yl]methylene]-2,3-dihydro-7-methoxy-2-oxo-1H-indole-1-acetate;

Methyl4-[[5-[(1,2-dihydro-1-methyl-2-oxo-3H-indol-3-ylidenyl)methyl]-2-propyl-1H-imidazol-1-yl]methyl]benzoate;

Methyl2,3-dihydro-3-[[3-[[4-(methoxycarbonyl)phenyl]methyl]-2-propyl-3H-imidazol-4-yl]methylene]-2-oxo-1H-indole-7-acetate;

(E)-3-[[3-[(4-carboxyphenyl)methyl]-2-propyl-3H-imidazol-4-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-1-aceticacid;

Benzoic acid,4-[[2-butyl-5-[[1-[(4-chlorophenyl)methyl]-2,3-dihydro-2-oxo-1H-indol-3-ylidene]methyl]-1H-imidazol-1-yl]methyl]-,(E)-;

1H-Indole-1-propanoic acid,3-[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-,(E)-;

Benzoic acid,4-[[2-butyl-5-[[2,3-dihydro-2-oxo-1-[(1H-tetrazol-5-yl)methyl]-1H-indol-3-ylidene]methyl]-1H-imidazol-1-yl]methyl]-,methyl ester, (E)-;

1H-Indole-1-propanoic acid,3-[[2-butyl-1-[[4-methoxycarbonyl)phenyl]methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-,ethyl ester, (E)-;

Benzoic acid,4-[[2-butyl-5-[[1-(cyanomethyl)-2,3-dihydro-2-oxo-1H-indol-3-ylidene]methyl]-1H-imidazol-1-yl]methyl]-,methyl ester, (E);

Benzoic acid,4-[[2-butyl-5-[[1-[2-(dimethylamino)ethyl-2,3-dihydro-2-oxo-1H-indol-3-ylidene]methyl]-1H-imidazol-1-yl]methyl]-,methyl ester, (E)-;

1H-Indole-1-acetic acid,3-[[2-butyl-1-[[4-(1H-tetrazol-5-yl)phenyl]methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-,methyl ester;

Benzoic acid,4-[[5-[(2,3-dihydro-1-methyl-2-oxo-1H-indol-3-ylidene)methyl]-2-propyl-4-(1H-pyrrol-1-yl)-1H-imidazol-1-yl]methyl-,methyl ester, (E)-;

Benzoic acid,4-[[2-butyl-5-(1-butyl-2,3-dihydro-2-oxo-1H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]-,methyl ester;

1H-Indole-1-acetic acid,2,3-dihydro-3-[[1-[[4-(methoxycarbonyl)phenyl]methyl]-2-propyl-4-(1H-pyrrol-1-yl)-1H-imidazol-5-yl]methylene]-2-oxo-,methyl ester, (E);

Benzoic acid,4-[[5-[[2,3-dihydro-1-(1-methylethyl)-2-oxo-1H-indol-3-ylidene]methyl]-2-propyl-1H-imidazol-1-yl]methyl]-,methyl ester, (Z)-;

Benzoic acid,4-[[5-[(1-butyl-2,3-dihydro-2-oxo-1H-indol-3-ylidene)methyl]-2-propyl-4-(1H-pyrrol-1-yl)-1H-imidazol-1-yl]methyl]-,methyl ester, (E)-;

Benzoic acid,4-[[2-butyl-5-[[2,3-dihydro-1-(2-methoxy-2-oxoethoxy)-2-oxo-1H-indol-3-ylidene]methyl]-1H-imidazol-1-yl]methyl]-,methyl ester;

1H-Indole-1-acetic acid,3-[[2-butyl-1-[[4-(1H-tetrazol-5-yl-phenyl]methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-,ethyl ester;

Benzoic acid,4-[[5-[(2,3-dihydro-2-oxo-1H-indol-3-ylidene)methyl]-2-ethyl-4-methyl-1H-imidazol-1-yl]methyl-(E)-;

2-(1H)-Isoquinolineacetic acid,3,4-dihydro-4-[[1-[[4-(methoxycarbonyl)phenyl]methyl]-2-propyl-1H-imidazol-5-yl]methylene]-1,3-dioxo-,methyl ester, (Z)-;

Benzoic acid,4-[[2-butyl-5-[2,3-dihydro-2-oxo-1H-indol-3-yl)methyl]-1H-imidazol-1-yl]methyl]-,methyl ester; and their pharmaceutically acceptable salts.

Both the E and Z isomers are within the scope of the invention.

The E-isomers (trans stereochemistry of the carbonyl and imidazolegroups) are generally more active and thus, are preferred over the Zisomers.

The compounds of the instant invention include solvates, hydroates, andpharmaceutically acceptable acid addition and/or base salts of thecompounds of Formula I above.

The term pharmaceutically acceptable acid addition salt is intended tomean a relatively nontoxic acid addition salt either from inorganic ororganic acids such as, for example, hydrochloric, hydrobromic,hydroiodic, sulfuric, phosphoric, acetic, citric, oxalic, malonic,salicylic, malic, benzoic, gluconic, fumaric, succinic, ascorbic,maleic, tartaric, methanesulfonic, and the like. The salts are prepared,when applicable, by contacting the free base form with a sufficientamount of the desired acid to produce a salt in the conventional manner.The free base forms may be regenerated by treating the salt form with abase.

When the compounds are in the free carboxylic acid form thepharmaceutically suitable salts also include both the metallic(inorganic) salts and organic salts; a list of which is given inRemington's Pharmaceutical Sciences, 17th Edition, 1985:1418. It is wellknown to one skilled in the art that an appropriate salt form is chosenbased on physical and chemical stability, flowability, hydroscopicity,and solubility. Preferred salts of this invention for the reasons citedabove include potassium, sodium, calcium, and ammonium salts.

The compounds of the present invention possess one or more chiralcenters and each center may exist in the R(D) or S(L) configuration. Thepresent invention includes all enantiomeric and epimeric forms as wellas the appropriate mixtures thereof.

The instant invention includes a process for the preparation ofcompounds of Formula I.

The term lower alkyl refers to straight or branched chain alkyl radicalscontaining from one to ten carbon atoms except where specifically statedincluding but not limited to methyl, ethyl, n-propyl, isopropyl,n-butyl, iso-butyl, sec-butyl, 2-methylhexyl, n-pentyl, 1-methylbutyl,2,2-dimethylbutyl, 2-methyl-pentyl, 2,2-dimethyl propyl, n-hexyl, andthe like.

The term halogen refers to bromine, chlorine, iodine, and fluorine.

The term cycloalkyl refers to cyclic alkyl groups containing three tosix carbon atoms.

The term aryl refers to phenyl and 1- or 2-naphthyl, unsubstituted orsubstituted by CH₃, OCH₃, OH, Br, Cl, F, NO₂, NH₂, N(CH₃)₂, SCH₃, SH.

Heteroaryl refers to 5- or 6-membered rings or 8-, 9-, or 10-memberedtwin rings containing one or more heteroatoms selected from N, O, S, andincludes but is not limited to: pyrrole, imidazole, thiophene, furane,pyridine, thiazole, indole, morpholine, isoquinoline.

Scheme I below illustrates one of the preparation of known startingmaterials (J Med Chem 1991; 34:1514-7, U.S. Pat. Nos. 4,207,324, and4,355,040), the disclosure of which is hereby incorporated by reference.

Scheme II outlines another procedure useful for compounds wherein R₃ isa group other than halo.

The 1-R¹ CH₂ -group is incorporated onto the 2-R² -Z-imidazole by knownprocedures, for example, by reaction with an R¹ --C₂ halide, mesylate oracetate, such as 2-chlorobenzyl bromide, in a suitable solvent, such asdimethylformamide (DMF), in the presence of a suitable acid acceptor,such as sodium alkylate, potassium or sodium carbonate, or a metalhydride, preferably sodium hydride, at a reaction temperature of25°-100° C., preferably 50° C. The resulting 1-R¹ CH₂ -2-R² imidazole ishydroxymethylated in the 5-position for example, by reacting withformaldehyde in the presence of sodium acetate in acetic acid to providethe 1-R¹ -CH₂ -2-R² X-5 hydroxymethylimidazole intermediates.

The hydroxymethyl group of the hereinbefore prepared intermediate isoxidized to an aldehyde by treatment with a suitable reagent, such asanhydrous chromic acid silica gel in tetrahydrofuran or, preferably,with activated manganese dioxide, in a suitable solvent such as benzene,or toluene, or preferably methylene chloride, at a temperature of25°-140° C., preferably at 25° C.

Alternatively, the 1-R¹ CH₂ -2-R² -5 hydroxymethylimidazoleintermediates are prepared by reacting an amidine, R₂ --C(═NH)--NH₂ suchas valeramidine, with dihydroxyacetone in liquid ammonia under pressureto give 2-R² -5-hydroxymethylimidazole (Imbach J. L., Jacquier R.,Lacombe J. M., Mawry G., Bull Soc Chim Fr 1971:1052). This intermediateis reacted with acetic anhydride to give 1-acetyl-5-acetoxymethyl-2-R²-imidazole. The diacetate intermediate is N alkylated, for example,using 2-chlorobenzyl triflate and the resulting 1-R¹ CH₂ -2-R²-5-acetoxymethylimidazole is treated with aqueous base, such as 10%sodium hydroxide solution, to give the 1-R¹ CH₂ -2-R²-5-hydroxymethylimidazole intermediate which can be oxidized as beforeto the aldehyde 2b (see Scheme III).

Scheme IV below illustrates the synthesis of the compounds ofstructure 1. Compounds of the structure 2 are reacted with the requisiteoxo-methylene substrate, for example, 6 under acid catalyzed (Method A)or base catalyzed (Method B) condition to afford 3. Compounds 3 aretreated with base, such as KOH, LiOH, or NaOH in aqueous alcohol ordiglyme, to yield the desired carboxylic acid 5. Alternatively,compounds 2 are treated with base to give acids 4 which are then reactedwith 6 to provide compounds 5. Method A uses acid such as, but notlimited to, acetic acid, propionic acid, etc., containing p-toluenesulfonic acid, β-alanine, anhydrous NaAc, trifluoro acetic anhydride,acetic anhydride, etc. Method B uses solvents such as, but not limitedto, ethanol, toluene, xylene-containing piperidine, Et₃ N, sodiummethoxide, etc.

The (E)- and (Z)-isomers are separated either at the ester stage(compound 3) by column chromatography or at the acid stage (compound 5)by crystallization.

For compounds where the substituted oxindoles are not easily accessibleare obtained from compound 3 via alkylation as shown in Scheme V.Compound 3 is treated with the requisite alkyl halide in the presence ofa base (for example, Cs₂ CO₃) in DMF to give compound of structure 7.This can be treated with NaOH in aqueous alcohol to give the desiredacid 8.

The 1-R¹ CH₂ -2-R² X-imidazol-5-carboxaldehydes are reacted with anappropriate phosphonate (Scheme VI). The phosphonates are prepared, forexample, from trialkyl phosphonoacetates by alkylation with anappropriate halide, mesylate or acetate in the presence of a suitablebase, such as sodium hydride, DBU in a suitable solvent, preferablyglyme at a reaction temperature of 25°-100° C., preferably at 55° C. Thereaction of the imidazol 5 carboxaldehydes with the phosphonates isperformed in the presence of a suitable base, such as a metal alkoxide,lithium hydride or, preferably, sodium hydride, in a suitable solvent,such as ethanol, methanol, ether, dioxane, tetrahydrofuran or,preferably glyme, at a reaction temperature of 10°-50° C., preferably,at 25° C., to provide a variable mixture of trans and cis, e.g., (E) and(Z). The trans and cis structures of the acids are readily determined byNMR by the NOE protocol, as well as by the biological activities since,generally, the trans (E)-isomers are the more potent isomers.

Compounds of structure (1) are also prepared as follows. The 1-R¹-(CH₂)-2-R² X-imidazol-5-carboxaldehydes are treated with the lithiumderivative of an active methylene substrate, such as 6. These lithioderivatives are prepared from the reaction of lithium diisopropylamidein as suitable solvent, preferably tetrahydrofuran, with an acid ester,such as ROOC-CH₂ -Y-phenyl, to generate the α-lithio derivatives at -78°to -10° C., preferably at -78° C., which are then treated with theimidazolcarboxaldehyde. The intermediates β-hydroxy group of theimidazole ester is converted to a mesylate or an acetate and themesylate, or preferably the acetate, is heated in a suitable solvent,such as toluene, with one to two equivalents of1,8-diazobicyclo[5.4.0]undec-7-ene, at 50°-110° C., preferably at 80°C., to afford compounds of structure (1). The (E)-isomer is thepredominate olefinic isomer. The acids are prepared from the esters bythe method described above.

The starting materials 6 are prepared by known procedures.

Another alternative procedure to prepare compounds of structure I isoutlined in Scheme VII. The 4-chloro-5-formyl imidazole is reduced togive the 5-formyl imidazole (10) which reacted with oxindole 9 (or 6) inthe presence of a base as before to give the condensation product 11.This is converted to the N-protected (for example, Boc, trityl, acetyl,POM, etc) imidazole derivative 12 by reacting with BOC. chloride in thepresence of a base in DMF. Compound 12 is converted to the targetcompound 3 by triflic anhydride/requisite benzyl alcohol method.

Scheme VIII outlines the synthesis of compound 2 wherein the esterfunctionality is replaced with a tetrazole moiety. p-Tolunitrile isconverted to the tetrazole compound via standard reaction conditionusing NaN₃ /NH₄ Cl/DMF. The tetrazole is protected with a trityl groupby the reaction of tritylchloride in the presence of Et₃ N in DMF. Thisis converted to the corresponding bromide which is then condensed withthe imidazole 1 as before to give the desired chloro. aldehyde. This isconverted to the corresponding hydrogen compound 13 by catalyticreduction. This is reacted with the oxindole to give compound 14 asdescribed before. This is converted to the free tetrazole compound 15 bytreatment with MeOH. Alternatively, compound 14 is alkylated tointroduce a substitution at the nitrogen by treatment with the desiredalkyl halide in presence of a base. Subsequent treatment with MeOH givescompound 16. In addition, compound 16, wherein R' is a CO₂ Me (or CO₂Et) group, is saponified to give the desired acid 17.

One example of the synthesis of the starting material where R₃ is aheterocycle is shown in Scheme IX. The requisite imidate-HCl is reactedwith ethyl amino cyano acetate (Shaw et al, Chemistry and Industry1981:542) in the presence of KOAc in methanol to give the 4-aminoimidazole-5-carboxylate derivative. This is treated with 2,5-dimethoxytetrahydrofuran in AcOH under refluxing condition to give the desiredpyrrole derivative. The ester moiety is converted to the carboxaldehyde18 in two steps which is used for N-benzylation as before.

Scheme X outlines a general procedure to prepare compounds of Formula Iwhere the double bond is reduced. ##STR8##

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets, and suppositories. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or tablet disintegrating agents. It can also be encapsulatingmaterial. In powders, the carrier is a finely divided solid which is inadmixture with the finely divided active compound. In the tablet theactive compound is mixed with a carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from 5 to 10% toabout 70% of the active ingredient. Suitable solid carriers aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, a low meltingwax, cocoa butter, and the like. The term "preparation" is intended toinclude the formulation of the active compound with encapsulatingmaterial as carrier providing a capsule in which the active component(with or without other carriers) is surrounded by carrier, which is thusin association with it. Similarly, cachets are included. Tablets,powders, cachets, and capsules can be used as solid dosage formssuitable for oral administration.

The compounds of the present invention may be administered orally,buccally, parenterally, by inhalation spray, rectally, or topically indosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants, and vehicles asdesired. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection, orinfusion techniques.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby solidify.

Liquified form preparations include solutions, suspensions, andemulsions. As an example may be mentioned water or water/propyleneglycol solutions for parenteral injection. Liquid preparations can alsobe formulated in solution in aqueous polyethyleneglycol solution.Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, i.e.,natural or synthetic gums, resins, methylcellulose, sodiumcarboxymethyl-cellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions, and emulsions. These particular solid form preparations aremost conveniently provided in unit dose form and as such are used toprovide a single liquid dosage unit. Alternately, sufficient solid maybe provided so that after conversion to liquid form, multiple individualliquid doses may be obtained by measuring predetermined volumes of theliquid form preparation as with a syringe, teaspoon, or other volumetriccontainer. When multiple liquid doses are so prepared, it is preferredto maintain the unused portion of said liquid doses at low temperature(i.e., under refrigeration) in order to retard possible decomposition.The solid form preparations intended to be converted to liquid form maycontain, in addition to the active material, flavorants, colorants,stabilizers, buffers, artificial and natural sweeteners, dispersants,thickeners, solubilizing agents, and the like. The liquid utilized forpreparing the liquid form preparation may be water, isotonic water,ethanol, glycerin, propylene glycol, and the like, as well as mixturesthereof. Naturally, the liquid utilized will be chosen with regard tothe route of administration, for example, liquid preparations containinglarge amounts of ethanol are not suitable for parenteral use.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, for example, packeted tablets, capsules, and powders invials or ampules. The unit dosage form can also be a capsule, cachet, ortablet itself, or it can be the appropriate number of any of these inpackaged form.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from 1 to 500 mg, preferably 5 to 100 mg according tothe particular application and the potency of the active ingredient. Thecompositions can, if desired, also contain other compatible therapeuticagents.

In therapeutic use as antihypertensive agents, the mammalian dosagerange for a 70 kg subject is from 0.1 to 500 mg/kg of body weight perday or preferably 1 to 500 mg/kg of body weight per day optionally individed portions. The dosages, however, may be varied depending upon therequirements of the patient, the severity of the condition beingtreated, and the compound being employed. Determination of the properdosage for a particular situation is within the skill of the art.Generally, treatment is initiated with smaller dosages which are lessthan the optimum dose of the compound. Thereafter the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day if desired.

The effectiveness of the compounds of the instant invention isdetermined by a test (RBAT₁) entitled Receptor Binding of AngiotensinII. In this in vitro test the inhibition of tritiated angiotensin IIbinding to rat liver membranes is measured (Dudley, D. T., et al,Molecular Pharmacology 1990;38:370-7).

    ______________________________________                                               Example                                                                              RBAT.sub.1                                                             Name   IC.sub.50, nM                                                   ______________________________________                                               1D     75                                                                     2B     610                                                                    2C     201                                                                    2D     86                                                                     2F     67                                                                     2G     746                                                                    3      170                                                                    3A     140                                                                    3B     120                                                                    3C     22                                                                     3F     123                                                                    3G     20                                                                     3H     52                                                                     3I     140                                                                    4      590                                                                    4A     640                                                                    4B     95                                                                     4C     358                                                                    4E     72                                                                     4E     72                                                                     4F     256                                                                    4G     64                                                                     4H     226                                                                    4I     300                                                                    4J     686                                                                    4K     110                                                                    4M     54                                                                     5      94                                                                     6      25                                                                     6A     12                                                                     7      5.7                                                                    8      47                                                                     9      98                                                                     10     53                                                              ______________________________________                                    

Based on the observations that ACE inhibitors are known to benefitpatients with heart failure, the instant compound which also interruptsthe renin angiotensin system (RAS), would show similar benefits.

The following examples are provided to enable one skilled in the art topractice the present invention. These examples are not intended in anyway to limit the scope of the invention but are illustrative thereof.

EXAMPLE 1 Ethyl4-[[2-butyl-5-(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate

A mixture of 0.8 g (2.85 mmol) of2-butyl-1-(4-carbethoxy)benzyl-5-formyl-imidazole, 0.3 g (2.85 mmol) ofoxindole and β-alanine (20 mg) in AcOH (15 mL) was heated at reflux for18 hours. AcOH was distilled off and the residue was treated with EtOAc.The solid (09.7 g) was filtered off and recrystallized from EtOAc togive 0.27 g of yellow solid (E-isomer), mp 272°-273° C.

Analysis calculated for C₂₆ H₂₇ N₃ O₃ : C, 72.71; H, 6.34; N, 9.78.

Found: C, 72.52; H, 6.41; N, 9.75.

MS (CI) 430 (m).

Second crop; (Z-isomer); 0.3 g; mp 169°-171° C.

Analysis Found: C, 72.62; H, 6.42; N, 9.54.

MS (CI) 430 (m). H NMR indicate the presence of 15% of E-isomer.

The following were prepared using the procedure described above.

EXAMPLE 1A Methyl 4-[2-butyl-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]-3-chlorobenzoate

E-isomer; mp 219°-220° C.; MS (CI) 450 (m).

Analysis calculated for C₂₅ H₂₄ ClN₃ O₃.H₂ O: C, 65.43; H, 5.49; N,9.16. Found: C, 65.43; H, 5.27; N, 9.08.

Z-isomer; mp 195°-196° C.; MS (CI) 450 (m).

Calculated for C₂₅ H₂₄ ClN₃ O₃.0.3 H₂ O: C, 65.95; H, 5.46; N, 9.15.Found: C, 65.95; H, 5.46; N, 9.15.

EXAMPLE 1B Methyl4-[[2-butyl-5-[(1,2-dihydro-5-methyl-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]-benzoate

Mixture of E- and Z-isomers; MS (CI) 430 (m).

Analysis calculated for C₂₆ H₂₇ N₃ O₃ : C, 72.71; H, 6.34; N, 9.78.Found: C, 72.47; H, 6.21; N, 9.56.

mp 195°-200° C.

EXAMPLE 1C Ethyl4-[[2-butyl-4-chloro-5-[(1,2-dihydro-6-methyl-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate

Mixture of E- and Z-isomer; MS (CI) 478 (m).

Analysis calculated for C₂₇ H₂₈ ClN₃ O₃ : C, 67.85; H, 5.90; N, 8.79.Found: C, 67.41; H, 6.07; N, 8.52.

EXAMPLE 1D Methyl4-[[2-propyl-5-[(1,2-dihydro-1-methyl-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]-benzoate

E-isomer; mp 181°-182° C.; MS (CI) 415 (m).

Analysis calculated for C₂₅ H₂₅ N₃ O₃ : C, 72.27; H, 6.06; N, 10.11.Found: C, 72.22; H, 5.94; N, 9.97.

Z-isomer; MS (CI) 415 (m); mp 146°-148° C.

Analysis calculated for C₂₅ H₂₅ N₃ O₃.0.53 H₂ O: C, 70.68; H, 6.18; N,9.89. Found: C, 70.65; H, 6.16; N, 9.82.

EXAMPLE 1E Methyl4-[[2-butyl-5-[(1,2-dihydro-4-methyl-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]-benzoate

Z-isomer; mp 205°-207° C.; MS (CI) 430 (m).

Analysis calculated for C₂₆ H₂₇ N₃ O₃ : C, 72.71; H, 6.34; N, 9.78.Found: C, 72.25; H, 6.13; N, 9.56.

EXAMPLE 1F Methyl4-[[2-butyl-5-(1,2-dihydro-7-methyl-2-oxo-3H-indol-3-ylidene)methyl]-1-imidazol-1-yl]methyl]-benzoate

E-isomer; mp 198°-200° C.; MS (CI) 430 (m).

Analysis calculated for C₂₆ H₂₇ N₃ O₃ : C, 72.71; H, 6.34; N, 9.78.Found: C, 72.33; H, 6.21; N, 9.63.

Z-isomer; mp 221°-223° C.; MS (CI) 430 (m).

Analysis calculated for C₂₆ H₂₇ N₃ O₃ : C, 72.71; H, 6.34; N, 9.78.Found: C, 72.67; H, 6.13; N, 9.88.

EXAMPLE 1G Methyl4-[[2-butyl-5-[(5-chloro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]-benzoate

Z-isomer; mp 238°-241° C.; MS (CI) 450 (m).

Analysis calculated for C₂₅ H₂₄ ClN₃ O₃.0.25 EtOAc: C, 66.17; H, 5.55;N, 8.90. Found: C, 65.77; H, 5.45; N, 9.02.

EXAMPLE 1H Methyl4-[[2-butyl-5-[(1,2-dihydro-7-methoxy-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]-benzoate

E-isomer; MS (CI) 446 (m).

Z-isomer; mp 190°-195° C.; MS (CI) 446 (m).

Analysis calculated for 0.45 EtOAc: C, 68.82; H, 6.36; N, 8.66. Found:C, 68.58; H, 5.94; H, 8.36.

EXAMPLE 1I Ethyl3-[[2-butyl-1-[[4-(methoxycarbonyl)phenyl]-methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-5-carboxylate

Z-isomer; MS (CI) 488 (m); mp 211°-215° C.

Analysis calculated for: C, 68.98; H, 6.00; N, 8.62. Found: C, 68.64; H,6.11; N, 8.49.

EXAMPLE 2 Ethyl4-[[2-butyl-4-chloro-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]-benzoate

A mixture of 0.87 g (2.5 mmol) of2-butyl-1-(4-carbethoxy)benzyl-4-chloro-5-formyl-imidazole), 0.33 g (2.5mmol) of oxindole and 0.1 mL of piperidine in toluene (30 mL) was heatedat reflux with a Dean-Stark apparatus for 24 hours. The solution wasdiluted with toluene, washed with water, dried, and stripped to give adark brown solid. This was purified via column chromatography (silicagel, hexane/ethyl acetate, 10% to 50%) to yield 0.75 g of a dark yellowfoam. MS (CI) 464 (m).

Analysis calculated for C₂₆ H₂₆ ClN₃ O₃ : C, 67.31; H, 5.65; N, 9.06.Found: C, 67.65; H, 5.58; N, 8.99.

¹ H NMR indicate a mixture of E-/Z-isomer ratio of 4/1.

EXAMPLE 2A Ethyl3-[[2-butyl-1-[[(4-methoxycarbonyl)phenyl]methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-1-acetate

Z(83%)/E(17%); mp 233°-235° C.; MS (CI) 502 (m).

Analysis calculated for C₂₉ H₃₁ N₃ O₅.0.72 H₂ O: C, 67.67; H, 6.36; N,8.15. Found: C, 67.66; H, 6.52; N, 8.15.

E(89%)/Z(11%); mp 200°-201° C.; MS (CI) 502 (m).

Analysis calculated for C₂₉ H₃₁ N₃ O₅ : C, 69.44; H, 6.23; N, 8.38.Found: C, 69.10; H, 6.34; N, 8.29.

EXAMPLE 2B Methyl4-[[(2-propyl-5-[1,2-dihydro-1-(methylaminocarbonyl)-2-oxo-3H-indol-3-ylidene]methyl]-1H-imidazol-1-yl]methylbenzoate

Z(78%)/E(22%); MS (FAB) 459 (m); mp 76°-80° C.

Analysis calculated for C₂₆ H₂₆ N₄ O₄.0.31 H₂ O: C, 67.29; H, 5.78; N,12.07. Found: C, 67.30; H, 5.82; N, 11.99.

E(71%)/Z(29%); MS (CI) 459 (m); mp 73°-76° C.

Analysis calculated for C₂₆ H₂₆ N₄ O₄.0.4 H₂ O: C, 67.05; H, 5.80; N,12.03. Found: C, 67.05; H, 5.89; N, 11.91.

EXAMPLE 2C Methyl4-[[2-butyl-5-1,2-dihydro-1-hydroxy-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate

Mixture of E- and Z-isomers. A mixture of the aldehyde (0.488 g; 1.63mM) and N-hydroxyoxindole (Kende AS, et al, Synthetic Comm 1990;20:2133)(0.25 g; 1.68 mM) in abs. EtOH (6.0 mL) is treated with 4 drops ofpiperidine and the solution is heated to reflux for 4.0 hours. Oncooling, the product crystallizes containing ethanol as solvent ofcrystallization. Yield 0.473 g 62.7%); mp 198°-200° C. MS (CI) 432 (m).

EXAMPLE 2D

(E)-4-[[-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylideny)methyl]-2-propyl-4-(1H-pyrrol-1-yl)-1H-imidazol-1-yl]methyl] benzoicacid

MS (FAB) 453 (m).

Analysis calculated for C₂₇ H₂₂ N₄ O₃ Na₂.0.43 H₂ O: C, 64.32; H, 4.57;N, 11.11. Found: C, 64.70, H, 4.97; N, 10.77.

EXAMPLE 2EMethyl-4-[[2-butyl-5-[1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate

MS (CI) 416 (m); mp 264°-265° C.

EXAMPLE 2F Benzoic acid,4-[[5-[[2,3-dihydro-1-(1-methylethyl)-2-oxo-1H-indol-3-ylidene]methyl]-2-propyl-1H-imidazol-1-yl]methyl]-,methyl ester, (Z)

By following the methodology of Example 2 and substituting the properlysubstituted oxindole in place of oxindole additional analogs wereobtained.

MS (CI) 444 (m);

Analysis calculated for C₂₇ H₂₉ N₃ O₃.0.5 tBuOH.0.4 H₂ O:

C, 71.89; H, 6.72; N, 9.25; Found: C, 71.94; H, 6.77; N, 9.10.

EXAMPLE 2G Methyl4-[[5-(1,2-dihydro-2-oxo-1-propyl-3H-indol-3-ylidenyl)methyl]-2-propyl-1H-imidazol-1-yl]methyl]benzoate

MS (CI) 444 (m).

Analysis calculated for C₂₇ H₂₉ N₃ O₃.0.5 H₂ O: C, 71.66; H, 6.68; N,9.29. Found: C, 71.64, H, 6.55; N, 9.19.

EXAMPLE 2H Benzoic acid,4-[[5-(2,3-dihydro-2-oxo-1H-indol-3-ylidene)methyl]-2-ethyl-4-methyl-1H-imidazol-1-yl]methyl]-(E)

By replacing the 5-formyl-imidazole in Example 2 with the 5-formylimidazole from Example 11D and following the methodology described inExample 2, the title compound was obtained. MS (CI) 387, (m).

Analysis calculated for C₂₃ H₂₁ N₃ O₃.0.8 H₂ O: C, 68.75; H, 5.67; N,10.46. Found C, 68.51; H, 5.53; N, 10.13.

¹ H NMR indicate 10% of the Z-isomer.

EXAMPLE 34-[[2-Butyl-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)-methyl]-1H-imidazol-1-yl]methyl]benzoicacid

A mixture of 0.4 g of compound 1 (E- and Z-isomer, Example 1) inmethanol (10 mL) and a solution of 80 mg of NaOH in 0.35 mL of water washeated at reflux for 4 hours. Methanol was stripped and the solution wasdiluted with water and extracted with EtOAc. The aqueous solution wasacidified to pH 4 and the solid was filtered, washed with water, anddried in a vacuum oven at 80° C. for 14 hours to give 0.35 g of theproduct, mp 237°-238° C.; MS (CI) 401 (m).

Analysis calculated for C₂₄ H₂₃ N₃ O3: C, 71.80; H, 5.77; N, 10.47.Found: C, 66.98; H, 5.66; N, 10.25.

The following were prepared by using the procedure described above.

EXAMPLE 3A(E)-4-[[2-Butyl-4-chloro-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)-1H-imidazol-1-yl]methyl]benzoicacid

MS (CI) 436 (m); crystallized from EtOAc to give analytically puresample, mp 241°-242° C.

Analysis calculated for C₂₄ H₂₂ ClN₃ O₃ : C, 66.13; H, 5.09; N, 9.64;Cl, 8.13. Found: C, 65.75; H, 5.06; N, 9.45; Cl, 8.20.

EXAMPLE 3B4-[[2-Butyl-5-[(1,2-dihydro-7-methoxy-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoicacid

E- and Z-isomer (1:1); MS (CI) 432 (m); mp 248°-251° C.

Analysis calculated for C₂₅ H₂₅ N₃ O₄.0.8 H₂ O: C, 67.34; H, 6.01; N,9.42. Found: C, 67.06; H, 5.98; N, 9.25.

EXAMPLE 3C3-[[2-Butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-1-aceticacid

E- and Z-mixture (1:1); MS (EI) 460 (m).

Analysis calculated for C₂₆ H₂₅ N₃ O₅.1.28 H₂ O: C, 64.74; H, 5.50; N,8.51.

EXAMPLE 3D3-[[2-Butyl-1-(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-5-carboxylicacid

E- and Z-isomer (1:1); MS (EI) 445 (m).

Analysis calculated for C₂₅ H₂₃ N₃ O₅.0.81 H₂ O: C, 65.27; H, 5.39; N,9.13. Found: C, 65.26; H, 5.33; N, 9.15.

EXAMPLE 3E4-[[2-Butyl-5-[(1,2-dihydro-5-methyl-2-oxo-3H-indol-3-ylidenemethyl]-1H-imidazol-1-yl]methyl]benzoicacid

E- and Z-isomer (1:1); MS (CI) 416 (m).

Analysis calculated for C₂₅ H₂₅ N₃ O₃.1.65 H₂ O: C, 67.44; H, 6.41; N,9.44. Found: C, 67.15; H, 6.02; N, 9.36.

EXAMPLE 3F4-[[2-Butyl-5-[(1,2-dihydro-1-methyl-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoicacid

Mixture of E- and Z-isomers. A mixture of the ester from Example 2C 126mg; 0.27 mM), MeOH (10 mL), and water (10 mL) is treated with 1N NaOH(1.5 mL) when the mixture turns into a dark solution. The solution isheated on a steam bath for 5 minutes and is then concentrated to a smallvolume, diluted with water, and filtered. The aqueous solution iscarefully acidified with acetic acid (1.5 mL) when the product slowlycrystallizes out as mono hydrate. It is filtered, washed with water, anddried. Yield 119 mg 99%); mp 185°-188° C. MS (FAB) 418 (M+1).

Analysis calculated for C₂₄ H₂₃ N₃ O₄.1 H₂ O: C, 66.19; H, 5.79; N,9.65. Found: C, 66.32; H, 5.67; N, 9.60.

EXAMPLE 3G 1H-Indole-1-propanoic acid,3-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-,(E)

MS (CI) 474 (m).

Analysis calculated for C₂₇ H₂₇ N₃ O₅.0.9 H₂ O: C, 66.22; H, 5.93; N,8.58. Found: C, 66.30; H, 5.82; N, 8.32.

EXAMPLE 3H4-[[2-butyl-5-[(1-butyl-1,2-dihydro-2-oxo-3H-indol-3-ylidenyl)methyl]-1-yl]methyl]-3-chlorobenzoicacid

MS(FAB) 492 (m).

Analysis calculated for C₂₈ H₃₀ ClN₃ O₃.CH₂ Cl₂.2.5 H₂ O: C, 56.00; H,6.00; N, 6.76. Found: C, 55.74; H, 5.99; N, 6.46.

EXAMPLE 3I4-[[-5-[(1,2-dihydro-2-oxo-1-propyl-3H-indol-3-yl-idenyl)methyl]-2-propyl-1H-imidazol-1-yl]methyl]benzoicacid

(FAB) 416 (m).

EXAMPLE 4 Benzoic acid,4-[[5-(1-butyl-2,3-dihydro-2-oxo-1H-indol-3-ylidene)methyl]-2-propyl-4-(1H-pyrrol-1-yl)-1H-imidazol-1-yl]methyl]-,methyl ester, (E)

To a solution of 0.46 g (1 mmol) of the methylester of compound fromExample 2D in DMF (6 mL) was added Cs₂ CO₃ (0.65 g, 2 mmol). Thisreaction mixture was stirred for 15 minutes followed by the addition ofa solution of nBuBr (0.27 g, 2 mmol) in DMF (5 mL). The solution wasstirred for 5 hours at room temperature. DMF was distilled under highvacuum, the residue was dissolved in water and the solution wasextracted with EtOAc. The extract was washed with water, dried, andstripped. The residue was triturated with ether/EtOAc to yield a solidwhich was filtered to give 0.35 g of the titled product,

MS 523 (m), mp 135°-136° C.

Analysis calculated for C₃₂ H₃₄ N₄ O₃ : C, 73.54; H, 6.56; N, 10.72.Found: C, 73.05; H, 6.51; N, 10.40.

The following were prepared by using the methodology described above.

EXAMPLE 4A Benzoic acid,4-[[-5-[(2,3-dihydro-1-methyl-2-oxo-1H-indol-3-ylidene)methyl]-2-propyl-4-(1H-pyrrol-1-yl)-1H-imidazol-1-yl]methyl]-,methyl ester (E)

MS (CI) 481 (m); mp 163°-164° C.

Analysis calculated for C₂₉ H₂₈ N₄ O₃.0.29 CH₂ Cl₂ : C, 69.64; H, 5.70;N, 11.09. Found: C, 70.02; H, 6.02; N, 10.70.

EXAMPLE 4B 1H-Indole-1-acetic acid,2,3-dihydro-3-[[1-[[4-(methoxycarbonyl)phenyl]methyl]-2-propyl-4-(1H-pyrrol-1-yl)-1H-imidazol-5-yl]methylene]-2-oxo-,methyl ester. (E)

Yellow foam; MS (CI) 539 (m).

Analysis calculated for C₃₁ H₃₀ N₄ O₅.0.64 EtOAc: C, 67.75; H, 5.62; N,9.61. Found: C, 67.36; H, 5.62; N, 9.42.

Replacing compound from Example 2D with 2E, and following the procedureof Example 4 using requisite alkyl halide additional analogs have beenprepared.

EXAMPLE 4C Benzoic acid,4-[[2-butyl-5-(1-butyl-2,3-dihydro-2-oxo-1H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]-,methyl ester

Yellow foam; MS (CI) 472 (m).

Analysis calculated for C₂₉ H₃₃ N₃ O₃.0.1 EtOAc: C, 73.50; H, 7.09; N,8.75. Found: C, 73.17; H, 7.26; N, 8.78.

EXAMPLE 4D Benzoic acid, 4-[[2-butyl-5-[[1-[2-(dimethylamino)ethyl]-2,3-dihydro-2-oxo-1H-indol-3-ylidene]methyl]-1H-imidazol-1-yl]methyl]-,methyl ester, (E)

Mixture of E and Z-isomers; MS (CI) 487 (m).

Analysis calculated for: C₂₉ H₃₄ N₄ O₃.0.73 CH₃ OH: C, 70.02; H, 7.30;N, 10.99. Found: C, 70.25; H, 7.13; N, 10.59.

EXAMPLE 4E 1H-Indole-1-propanoic acid,3-[[2-butyl-1-[[4-(methoxycarbonyl)phenyl]methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo,ethyl ester, (E)

MS (CI) 516 (m).

Analysis calculated for C₃₀ H₃₃ N₃ O₅.0.44 MeOH: C, 69.02; H, 6.61; N,7.93. Found: C, 68.76; H, 6.33; N, 7.99.

EXAMPLE 4F Benzoic acid 4-[[2-butyl-5-[[1-[(4-chlorophenyl)methyl]-2,3-dihydro-2-oxo-1H-indol-3-ylidene]methyl]-1H-imidazol-1-yl]methyl]-,(E)

MS (CI) 526 (m).

Analysis calculated for C₃₁ H₂₈ N₃ O₃ Cl.0.2 H₂ O: C, 70.30; H, 5,40; N,7.93. Found: C, 70.27; H, 5.45, N, 8.03.

EXAMPLE 4G Benzoic acid,4-[[2-butyl-5-[[2,3-dihydro-1-(2-methoxy-2-oxoethoxy)-2-oxo-1H-indol-3-ylidene]methyl]-1H-imidazol-1-yl]methyl]-,methyl ester

By substituting compound from Example 2D with compound 2C in Example 4and using methyl bromoacetate, the above target compound was obtained.

(MS (CI) 504 (m).

Analysis calculated for C₂₈ H₂₉ N₃ O₆.0.5 H₂ O: C, 66.79; H, 5.80; N,8.34. Found: C, 65.61; H, 5.90; N, 8.20.

EXAMPLE 4H Benzoic acid,4-[[2-butyl-5-[[1-(cyanomethyl)-2,3-dihydro-2-oxo-1H-indol-3-ylidene]methyl]-1H-imidazol-1-yl]methyl]-,methyl ester. (E)

Z-isomer; MS (CI) 455 (m); mp 193°-195° C.

Analysis calculated for C₂₇ H₂₆ N₄ O₃ : C, 71.35; H, 5.77; N, 12.33.Found: C, 71.04; H, 5.71; N, 12.15.

E-isomer; MS (CI) 455 (m); mp 124°-127° C.

Analysis calculated for C₂₇ H₂₆ N₄ O₃ : C, 71.35; H, 5.77, N, 12.33.Found: C, 71.04, H, 5.63, N, 12.11.

EXAMPLE 4I Ethyl(Z)-(+)-2,3-dihydro-3-[[3-[[4-(methoxycarbonylphenyl]methyl]-2-propyl-3H-imidazol-4-yl]methylene]-4-methyl-2-oxo-α-propyl-1H-indole-1-acetate

By substituting compound from Example 2D with compound 1E in Example 4and using ethyl 2-bromopentanoate, the title compound was obtained.

MS (CI) 544 (m); mp 154°-156° C.

Analysis calculated for C₃₂ H₃₇ N₃ O₅ : C, 70.70; H, 6.86; N, 7.73.Found: C, 70.38; H, 6.93; N, 7.55.

EXAMPLE 4J Methyl(Z)-2,3-dihydro-3-[[3-[[4-methoxycarbonylphenyl]methyl]-2-propyl-3H-imidazol-4-yl]methylene]-4-methyl-2-oxo-1H-indole-1-acetate

By substituting compound from Example 2D with compound 1E in Example 4and using methyl bromoacetate, the title compound was obtained. MS (CI)488 (m); mp 228°-230° C.

Analysis calculated for C₂₈ H₂₉ N₃ O₅.1.2 H₂ O: C, 66.05; H, 6.22; N,8.27. Found: C, 65.85; H, 5.93; N, 7.97.

EXAMPLE 4K Methyl4-[[2-butyl-5-(1-butyl-1,2-dihydro-2-oxo-3H-indol-3-yliden)methyl]-1H-imidazolyl]methyl]-3-chlorobenzoate

By substituting compound from Example 2D with compound 1A in Example 4,the above compound was obtained. MS (CI) 505 (m).

EXAMPLE 4L Ethyl (Z)-3-[[2-butyl-3-[[4-(methoxycarbonyl)phenyl]methyl]-3H-imidazol-4-yl]methylene]-2,3-dihydro-7-methoxy-2-oxo-1H-indole-1-acetate

By substituting compound from Example 2D with compound 1H in Example 4,and using ethyl bromoacetate, the title compound was obtained.

MS (CI) 532, (m), mp 157°-158° C.

Analysis calculated for C₃₀ H₃₃ N₃ O₆.0.34 MeOH: C, 67.17; H, 6.38; N,7.90. Found: C, 66.78; H, 6.15; N, 7.72.

The following compounds have been prepared by methods similar to thoseabove:

4-[[2-butyl-5-[(1,2-dihydro-7-methyl-2-oxo-3H-indol-3-ylidenyl)methyl]-1H-imidazol-1-yl]methyl]benzoic acid

Methyl4-[[5-[(1,2-dihydro-1-methyl-2-oxo-3H-indol-3-ylidenyl)methyl]-2-propyl-1H-imidazol-1-yl]methyl]benzoate

Methyl 2,3-dihydro-3-[[3-[[4-(methoxycarbonyl)phenyl]methyl]-2-propyl-3H-imidazol-4-yl]methylene]-2-oxo-1H-indole-7-acetate

EXAMPLE 5 Benzoic acid,4-[[2-butyl-5-[2,3-dihydro-2-oxo-1-(1H-tetrazol-5-ylmethyl)-1H-indol-3-ylidene]methyl]-1H-imidazol-1-yl]methyl]-,methyl ester. (E)

A mixture of 0.5 g (1.1 mM) of the nitrile from Example 4H, NaN₃ (0.14g, 2.2 mM) and 0.12 g (NH₄ Cl) in DMF (10 mL) was heated at 95° C. for4.5 hours. DMF was distilled under vacuum and the residue was treatedwith water. The solution was adjusted to pH 2 when an orange coloredsolid precipitated. It was filtered, washed successively with water andether, and finally air-dried to give 0.38 g of a solid. ¹ H NMR indicatemostly Z-isomer. HPLC indicate a mixture of 82% (Z) and 15% (E)-isomer.MS (CI) 498 (m). The filtrate was adjusted to pH 5 and the solid wasfiltered, washed with successively with water and ether, and air-driedto give 50 mg of a yellow solid. ¹ H NMR idicate mostly E-isomer. HPLCindicate a mixture of 82.5% (E) and 4.6% (Z)-isomer. MS (CI) 498 (m).

EXAMPLE 6 1 H-Indole-1-acetic acid,3-[[2-butyl-1-[[4-(1H-tetrazol-5-yl)phenyl]methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-,methyl ester

A mixture of 3.58 g (6.5 mmol) of the compound from Example 14, oxindole(0.91 g, 6.8 mmol) and piperidine (0.1 g) in toluene (35 mL) was heatedunder reflux for 18 hours under N₂. The reaction mixture was cooled andfiltered to give a solid. The filtrate was evaporated to remove toluene.This residue was combined with the solid and chromatographed [CH₂ Cl₂-CH₂ Cl₂ /EtOAc(1:1)] to separate E- (2.1 g) and Z-isomer (1.2 g) of thedesired product.3-[[2-butyl-3-[[4-[2-(triphenylmethyl)-2H-tetrazol-5-tetrazol-5-yl]phenyl]methyl]-3H-imidazol-4-yl]methylene]-1,3-dihydro-2H-indol-2-one.

A mixture of 0.45 g (0.67 mmol) of the above oxindole, CS₂ CO₃ (4.79 g,14.7 mmol) and methyl bromoacetate ((0.11 g, 0.7 mmol in DMF (10 mL) wasstirred at room temperature for 2 hours. Upon usual work up andpurification [chromatography, CH₂ Cl₂ /Hexane (10%)-CH₂ Cl₂ /EtOAc(20%)]gave 0.9 g of the target compound. Methyl3-[[2-butyl-3-[[4-[2-(triphenylmethyl)-2-H-tetrazol-5-yl]phenyl]methyl]-3H-imidazol-4-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-1-acetate

A solution of the above trityltetrazole compound (0.9 g) in MeOH (12 mL)was heated under reflux for 16 hours. The reaction mixture was cooled to0° C. and filtered. The residue was washed with small volume of methanoland air-dried to give the tetrazole derivative (0.4 g). MS (CI) 498 (m),mp 222°-231° C.

Analysis calculated for C₂₇ H₂₇ N₇ O₃.0.6 H₂ O: C, 63.79; H, 5.59; N,19.29. Found: C, 64.19; H, 5.42; N, 18.82.

EXAMPLE 6A 1H-Indole-1-acetic acid,3-[[2-butyl-1-[[4-(1H-tetrazol-5-yl)phenyl]methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-,ethyl ester

The title compound was analogously prepared. MS (CI) 511 (m); mp185°-188° C.

Analysis calculated for C₂₈ H₂₉ N₇ O₃.0.63 H₂ O.0.51 EtOAc; C, 63.55; H,6.11; N, 17.24. Found: C, 63.54; H, 5.81; N, 17.23.

EXAMPLE 73-[2-butyl-3-[[4-(1H-tetrazol-5-yl)phenyl]methyl]-3H-imidazol-4-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-1-aceticacid

The compound from Example 6 was suspended in MeOH (8 mL) to which wasadded a solution of dilute NaOH (0.103 g in 1 mL H₂ O). The clearsolution was stirred at room temperature for 2 hours. MeOH was removed,the residue was diluted with water, and the solution adjusted to pH 4.The precipitate was filtered, washed with small volume of water, anddried under vacuum at 80° C. for 3.5 hours. ¹ H NMR indicate a 1:1mixture of E- and Z-isomer of the desired product.

MS (CI) 484 (m), mp 212°-215° C.

Analysis calculated for C₂₆ H₂₅ N₇ O₃.0.74 H₂ O: C, 63.03; H, 5.19; N,19.34. Found: C, 62.85; H, 5.37%; N, 19.73.

EXAMPLE 8 2(1H)-Isocuinolineacetic acid,3,4-dihydro-4-[[1-[[4-(methoxycarbonyl)phenyl]methyl]-2-propyl-1H-imidazol-5yl]methylene]-1,3-dioxo-,methyl ester, (Z)

A mixture of glycine methyl ester hydrochloride (0.77 g, 6.17 mmol),homophthalic anhydride (1.0 g, 6.17 mmol) and K₂ CO₃ (0.86 g) in toluene(60 mL) was heated under reflux with a Dean-Stark apparatus for 8 hours.The reaction mixture was cooled, filtered, and the residue was washedthoroughly with EtOAc. The filtrate and the washings were evaporated togive 1.15 g of a yellow solid. MS (EI) 233 (m). This was used as is forthe next step.

A mixture of 0.75 g (2.62 mmol) of the aldehyde from Example 11B and 0.6g (2.62 mmol) of the above-homophthalimide-derivative in toluene (50 mL)containing catalytic amount of piperidine was heated under reflux for 18hours. Toluene was distilled under vacuum and the residuechromatographed (CH₂ Cl₂ /Acetone 2-7%) to give 0.9 g of a bright orangesolid. ¹ H NMR indicate 95% of the Z-isomer. MS (CI) 502, (m).

Analysis calculated for C₂₈ H₂₇ N₃ O₆ : C, 67.06; H, 5.43; N, 8.58.Found: C, 67.07; H, 5.37; N, 8.22.

EXAMPLE 9(Z)-3-[[3-[(4-carboxyphenyl)methyl]-2-propyl-3H-imidazol-4-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-1-aceticacid(E)-3-[[3-(4-carboxyphenyl)methyl]-2-propyl-3H-imidazol-4-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-1-aceticacid

A solution of 0.26 g (1.36 mmol) of 2,3-dihydro-2-oxo-1H-indole-1-aceticacid (prepared by saponification of 2,3-dihydro-2-oxo 1H-indole-1-aceticacid, ethyl ester) and 0.37 g (1.36 mmol) of compound from Example 11Cin (5 mL) of acetic acid containing 10 mg of β-alanine was refluxed for18 hours. The solution was cooled and the precipitate was filtered. Theresidue was washed with hexane and subjected to fractionalcrystallization from isopropyl alcohol to give E- and Z-isomers.Z-isomer; orange solid; mp 290°-291° C. (dec). MS (CI) 446 (m).

Analysis calculated for C₂₅ H₂₃ N₃ O₅.0.53 H₂ O: C, 65.99; H, 5.33; N,9.33. Found: C, 65.60; H, 4.74; N, 8.96.

E-isomer; yellow solid, mp 198°-200° C. MS (CI) 446 (m).

Analysis calculated for C₂₅ H₂₃ N₃ O₅.0.9 H₂ O: C, 65.04; H, 5.41; N,9.10. Found: C, 64.88; H, 5.44, N, 9.06.

EXAMPLE 10 Benzoic acid,4-[[2-butyl-5-[(2,3-dihydro-2-oxo-1H-indol-3-yl)methyl]-1H-imidazol-1-yl]methyl]-,methyl ester, (±)

A solution of (0.5 g) of the compound from Example 2E in AcOH (15 mL)containing Ra/Ni (0.5 g) was subjected to catalytic reduction. HOAc wasdistilled under high vacuum and the residue was taken up in EtOAc. TheEtOAc solution was washed with NaHCO₃ followed by water, dried, andevaporated to yield an off-white foam. It was chromatographed (CH₂ Cl₂/MeOH, 5-10%) to give 0.29 g of the desired title compound. MS (CI) 417(m).

Analysis calculated for C₂₅ H₂₇ N₃ O₃.0.5 H₂ O: C, 70.40; H, 6.62; N,9.85. Found: C, 70.04; H, 6.47; N, 9.62.

Synthesis of the requisite 5-formyl-imidazole derivatives.

EXAMPLE 11

Ethyl 2-butyl-4-[[5-(formyl)-1H-imidazol-1-yl]methyl]benzoate wasprepared according to the procedure described in U.S. Pat. No.4,207,324.

2-Butyl-4-chloro-5-formyl-imidazole

A mixture of 2-butyl-4-chloro-5-hydroxymethyl-imidazole 20 g (0.1 mol)and MnO₂ (46.1 g, 0.53 mol) in THF (500 mL) was heated at reflux for 4hours. The reaction mixture was cooled and filtered through a bed ofcelite and washed thoroughly with hot THF. The filtrate and the washingswere concentrated under reduced pressure to give 18.7 g of a solid. Itwas chromatographed using CH₂ Cl₂ /MeOH (2%) as eluant to give 14 g of asolid; mp 95°-96° C.

A mixture of the above aldehyde (1.86 g, 0.01 mol) and CS₂ CO₃ (7.17 g,0.02 mol) in DMF (20 mL) was stirred for 10 minutes. To this mixture wasadded a solution of (4-carbethoxy)benzylbromide (2.7 g, 0.011 mol) inDMF (10 mL) and the resulting mixture was stirred for 2 hours. DMF wasdistilled, the residue was treated with water, and the mixture wasextracted with EtOAc. The EtOAc solution was washed with brine, dried,and evaporated. The residue was chromatographed (CH₂ Cl₂ /EtOAc, 10-15%)to give an oil (2.7 g). MS (CI) 345 (m).

Analysis calculated for C₁₈ H₂₁ ClN₂ O₃ : C, 61.98; H, 6.07; N, 8.03.Found: C, 61.65; H, 6.09; N, 7.84.

A solution of the above 4-chloro-imidazole derivative (1.18 g) in EtOH(75 mL) containing KOAc (0.33 g) was subjected to catalytic reduction inpresence of 5% Pd-C to give the title compound as an oil (0.8 g). MS314, (m).

The following compounds were prepared in an analogous manner.

EXAMPLE 11A Methyl2-butyl-4-[[5-(formyl)-1H-imidazol-1-yl]methyl]benzoate EXAMPLE 11BMethyl 2-propyl-4-[[5-(formyl)-1H-imidazol-1-yl]methyl]benzoate EXAMPLE11C

2-Propyl-4-[[5-(formyl)-1H-imidazol-1-yl]methyl]benzoic acid wasobtained from 11B by saponfication.

EXAMPLE 11D Methyl4-[[2-ethyl-5-(formyl)-4-methyl-1H-imidazol-1-yl]methyl]benzoate

Methyl 4-[[2-ethyl-4-methyl-1H-imidazol-1-yl]methyl]benzoate compoundwas prepared from 2-ethyl-4-methyl-imidazole and(4-carbmethoxy)benzylbromide in an analogous fashion as described inExample 11. A solution of the above imidazole (2.17 g, 8.14 mmol), NaOAc1.17 g), 37% HCHO (10 mL), and AcOH (1.2 mL) was heated under reflux for22 hours. The solution was evaporated under vacuo, and the residue wasstirred with 10 mL of 20% NaOH solution for 2 hours. It was diluted withwater and the solution was extracted with CH₂ Cl₂. The extract waswashed with water, dried, and evaporated to an oil. It waschromatographed (CH₂ Cl₂ /MeOH, 2-5%) to give 1.0 g of the desiredhydroxymethyl compound as a foam. MS (CI) 288 (m).

A solution of the above hydroxymethyl imidazole derivative (1.0 g) wasoxidized with MnO₂ (1.5 g) in CH₂ Cl₂ (10 mL) as before. The product waspurified by chromatography (CH₂ Cl₂ /MeOH, 2%) to give the titlecompound (0.73 g) as a highly viscous gum which crystallized onstanding, MS (CI) 286 (m).

EXAMPLE 11E 2-Ethyl-4-[[5-(formyl)-1H-imidazol-1-yl]methyl]benzoic acid

A solution of the above ester from Example 11D in MeOH (4 mL) and 4N KOH(1.3 mL) was stirred at room temperature for 18 hours. MeOH was removed,the residue was treated with water, and the solution was adjusted to pH5. It was extracted with EtOAc and the extract was dried and evaporatedto give a pale yellow solid which was used as is for condensation withoxindole.

EXAMPLE 12 Ethyl4-[[5-formyl-2-procyl-4-(1H-pyrrol-1-yl)-1H-imidazol-1-yl]methyl]benzoateEthyl 4-amino-2-propylimidazole-5-carboxylate

A mixture of methyl propionimidate hydrochloride (4.8 g), ethyl2-amino-2-cyanoacetate oxalate (4.0 g), anhydrous sodium acetate (9.1g), and absolute ethanol (75 mL) was stirred at room temperature for 18hours. Solids were removed by filtration and the filtrate wasevaporated. The residue was partitioned between ethyl acetate and water.The ethyl acetate layer was washed with saturated NaCl, dried overMgSo₄, and evaporated. Flash chromatography on silica gel, eluting witha gradient of dichloromethane-ethyl acetate (75:25) to ethyl acetategives the title compound (2.7 g) as a pale yellow solid, mp 111°-114°C.; MS (DEI) 211 (m).

Ethyl 2-propyl-4-(1H-pyrrol-1-yl)imidazole-5-carboxylate

A solution of ethyl 4-amino-2-propylimidazole-5-carboxylate from above(9.34 g, 47 mmol) and sodium acetate (23.2 g) in acetic acid (100 mL)was heated to reflux and treated with 2,5-dimethoxy-tetrahydrofuran(6.75 mL, 52 mmol). The reaction was held at reflux for 30 minutes, thencooled back to room temperature with an ice bath. The majority of theacetic acid was evaporated under reduced pressure, then the residue waspartitioned between ethyl acetate and 10% aqueous K₂ CO₃ (120 mL) each.The organic layer was dried over MgSO₄ and evaporated. The residue waspurified by flash chromatography on silica gel, eluting with CH₂ Cl₂ -ethyl acetate (80:20). Evaporation of solvents gave a solid which wasrecrystallized from hexane/EtOAc (1:1) to give 7.4 g of the titlecompound, mp 134°-135° C.; MS (CI), 248 (m+1).

2-Propyl-5-(1H-pyrrol-1-yl)-1H-imidazole-4-methanol

Dissolved 11.77 mM (2.91 g) of the imidazole ester compound from abovein 60 mL of dry THF followed by dropwise addition of 12 mL of 1M lithiumaluminum hydride in ether over a period of 20 minutes. The resultingreaction was allowed to stir overnight at room temperature. The reactionmixture was treated with 20 mL saturated aqueous ammonium sulfateresulting in a solid white precipitate which was filtered and washedwell with ethyl acetate. The filtrate and the washings were then washedwith water, brine, and then dried over MgSO₄. Filtering off the dryingagent and evaporating off the solvent gave a white solid which wascrystallized from an 8:1 mixture of heptane and ethyl acetate to give1.48 g (61.4%) of a white solid, mp 155°-158° C.; MS (CI) 205 (m).

2-propyl-5-(1H-pyrrol-1-yl)-1H-imidazole-4-carboxaldehyde

Dissolved 6.63 mM 1.36 g) of the imidazole alcohol compound in 60 mL ofTHF, followed by addition of 2.87 g (5 eq) of activated manganesedioxide while stirring vigorously. The resulting black suspension washeated to reflux for 5 hours then filtered warm through a pad of celite.The solids were washed well with ethyl acetate resulting in a yellowfiltrate that when evaporated gave a beige solid. This crude solid wasrecrystallized from hexane/ethyl acetate (10:1) to give 0.74 g (54.9%)of a white solid, mp 118.5°-10° C.

Analysis calculated for C₁₁ H₁₃ N₃ O: C, 65.01; H, 6.45; N, 20.67.Found: C, 64.92; H, 6.29; N, 20.30.

MS (CI) 203 (m).

By substituting the 5-formyl-imidazole compound in Example 11 with theabove 5-formyl-imidazole and following the procedure described inExample 11, the title compound was obtained as an oil, MS (CI) 351 (m).

EXAMPLE 13 5-[4-(Bromomethyl)phenyl]-2-(triphenylmethyl)-2H-tetrazole5-(4-Methylphenyl)-1H-tetrazole

A solution of 4-toluenitrile (52.09 g, 0.44 mol), NaN₃ (57.8 g 0.87 mol)and NH₄ Cl (47.62 g, 0.89 mol) in DMF (150 mL) was heated at 95° C. for18 hours. The reaction mixture was cooled, diluted with water, andacidified with HCl. The solid was filtered, washed with water, and driedunder vacuum at 70° C. for 4 hours to give the title compound; mp243°-244° C.; MS (CI) 161 (m+1).

5-(4-Methylphenyl)-2-(triphenylmethyl)-2H-tetrazole

Tritylchloride (112.4 g, 0.4 mol) was added to a solution of the abovetetrazole (68 g, 0.4 mol) and Et₃ N (61.4 g, 0.44 mol) in DMF (2500 mL)with stirring. The reaction mixture was stirred for 16 hours andfiltered. The residue was thoroughly washed with DMF. The filtrate andthe washings were evaporated under vacuum and the residue was taken upin large volume of EtOAc. The EtOAc solution was washed with water,dried, and evaporated to give 165 g of the desired compound; mp172°-175° C.

5-[4-(Bromomethyl)phenyl]-2-(triphenylmethyl)-2H-tetrazole

A mixture of the above compound (100 g, 0.248 mol) and NBS (44.2 g, 0.24mol) in CCl₄ (1 L) containing catalytic amount of VAZO-52 (0.5 g) washeated under reflux for 4 hours. Additional quantity of NBS (4.4 g) wasadded and the reaction mixture was heated for 45 minutes. It wasfiltered and the filtrate was evaporated to give an orange solid. It wasrecrystallized from EtOAc/Hexane (2:1) to give 68 g of the titlecompound as a white solid, mp 165°-172° C.

Analysis calculated for C₂₇ H₂₁ BrN₄ ; C, 67.37; H, 4.40; N, 11.64.Found: C, 66.90; H, 4.20; N, 11.13.

EXAMPLE 142-Butyl-5-chloro-3-[[4-[2-(triphenylmethyl)-2H-tetrazol-5-yl]phenyl]methyl]-3H-imidazole-4-carboxaldehyde

The bromomethyl derivative from Example 13 was used to alkylate2-butyl-4-chloro-5-formyl-imidazole by following the procedure describedin Example 11 to give the desired compound as a white solid (23 g); mp154°-157° C., MS (CI), 587 (m-1);

Analysis calculated for C₃₅ H₃₂ N₆ ClO; C, 71.48; H, 5.48; N, 14.29.Found: C, 71.36; H, 5.21; N, 14.15.

2-Butyl-3-[[4-[2-(triphenylmethyl)-2H-tetrazol-5-yl]phenyl]methyl]-3H-imidazole-4-carboxaldehyde

17.3 g of the chloro compound was reduced in presence of 5% Pd-C asdescribed in Example 11. The crude material was purified viachromatography [CH₂ Cl₂ /Hexane (20%) CH₂ Cl₂ /EtOAc(20%)] to give thedesired material; mp 176°-177° C; MS (CI), 554 (m);

Analysis calculated for C₃₅ H₃₄ N₆ O: C, 75.92; H, 6.01; N, 15.18.Found: C, 75.83; H, 5.97; N, 15.26.

EXAMPLE 15

The oxindoles were either commercially available or were prepared byfollowing known literature methods.

1,3-Dihydro-1-propyl-2H-indol-2-one (Walker, et al, J Med Chem1970;13:983-85).

2,3-Dihydro-N-methyl-2-oxo-1H-indole-1-carboxamide, mp 159°-162° C.

2,3-Dihydro-2-oxo-1H-indole-7-acetic acid, ethyl ester, mp 145°-146° C.

1,3-Dihydro-1-methyl-2H-indol-2one.

1,3-Dihydro-1-(1-methylethyl)-2H-indol-2-one; waxy solid.

Analysis calculated for C₁₁ H₁₃ NO: C, 75.40; H, 7.48; N, 7.99. Found:C, 75.60; H, 7.46; N, 7.45. (Andreani, et al, Fffarmaco Ed Sci1977;32:703.05).

1-Hydroxyoxindole; mp 198°-202° C. prepare by the literature procedure(Kende AS, Thurston J, Syn Comm 1990;20:2133).

2,3-Dihydro-2-oxo-1H-indole-1-acetic acid, ethyl ester.

EXAMPLE 16 (Z) Ethyl3-[[2-butyl-[1-[[4-(methoxycarbonyl)phenyl]methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-1-acetate

A mixture of 1 g of 2-butyl imidazole-4-carboxaldehyde and2,3-dihydro-2-oxo-1H-indole-7-acetic acid, ethyl ester (1.5 g) intoluene (20 mL) containing 0.6 mL of piperidine was heated under refluxfor 18 hours. Toluene was distilled under vacuum and the residue wascrystallized from hexane/ethyl acetate to give 2.0 g of the desiredproduct; mp 118°-119° C., MS (CI), 354 (m);

Analysis calculated for C₂₀ H₂₃ N₃ O₃ ; C, 667.97; H, 6.56; N, 11.89.Found: C, 68.15; H, 6.62; N, 12.07.

BOC anhydride (1.9 g, 8.7 mmol) was added to a solution of the aboveimidazole product (2.0 g, 5.6 mmol) and Et₃ N (6.2 mmol) in CH₂ Cl₂ (20mL) and the reaction mixture was stirred at room temperature for 16hours. The solution was washed with water, brine, and dried overanhydride MgSO₄, and stripped to give a solid which was recrystallizedfrom hexane/EtOAc to give a yellow solid. MS (CI), 454 (m);

Analysis calculated for C₂₅ H₃₁ N₃ O₅.0.4 H₂ O; C, 65.17; H, 6.96; N,9.12. Found: C, 65.31; H, 6.79; N, 8.72.

To a solution of triflic anhydride (0.74 mL, 4.4 mmol) in CH₂ Cl₂ (20mL) at -78° C. was added dropwise a solution of4-(carbomethoxy)benzylalcohol (0.7 g, 4.2 mmol) and diisopropylethylamine (0.8 mL, 4.6 mmol) in CH₂ Cl₂ (10 mL) under nitrogenatmosphere. The mixture was stirred for additional 15 minutes followedby the addition of a solution of the above BOC imidazole derivative (1.9g, 4.2 mmol) in CH₂ Cl₂ (10 mL). The solution was allowed to warm toroom temperature and stirred for 16 hours. The solution was diluted withCH₂ Cl₂ and washed with water, brine, dried over anhydrous MgSO₄, andstripped. The residue was dissolved in CH₂ Cl₂ and filtered to give 0.43g of the title product; mp 207°-209° C.; MS (CI), 502 (m): The filtratewas chromatographed (EtOAc/CH₂ Cl₂ (4:1 )--EtOAc) to give 0.9 g ofadditional product. This was identical to the compound from Example 2A.

EXAMPLE 17 Ethyl3-[[2-butyl-1-[[4-[1H-tetrazol-5-yl]phenyl]methyl]-1H-imidazo-5-yl]methylene]2,3-dihydro-2-oxo-1H-indole-1-acetate

A mixture of 2.0 g of5-[4-(bromomethyl)phenyl]-2-(triphenylmethyl)-2H-tetrazole from Example13 and 1N NaOH (5 mL) in THF (20 mL) was stirred for 24 hours. Thesolvent was evaporated and the aqueous solution extracted with EtOAc.The organic layer was washed with water, dried, and evaporated to give1.8 g of 5-[4-(hydroxymethyl)phenyl]-2-(triphenylmethyl)-2H-tetrazolewhich was used as is for the next step; MS (EI), 418 (m).

By following the procedure described in Example 16 and using the above5-[4-(hydroxymethyl) phenyl]-2-(triphenylmethyl)-2H-tetrazole in placeof 4-(carbomethoxy)benzyl alcohol, the compound ethyl3-[[2-butyl-3-[[4-[2-(triphenylmethyl)-2H-tetrazol-5-yl]phenyl]methyl]-3H-imidazol-4-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-1-acetatewas obtained.

To a solution of triflic anhydride (0.74 mL, 4.4 mmol) in CH₂ Cl₂ (20mL) at -78° C. was added dropwise a solution of5-[4-(hydroxymethyl)phenyl]-2-(triphenylmethyl)-2H-tetrazole (1.75 g,4.2 mmol) and diisopropyl ethylamine (0.8 mL, 4.6 mmol) in C-₂ Cl₂ (10mL) under nitrogen atmosphere. The mixture was stirred for additional 15minutes followed by the addition of a solution of the BOC imidazolederivative from Example 16 (1.9 g, 4.2 mmol) in CH₂ Cl₂ (10 mL). Thesolution was allowed to warm to room temperature and stirred for 16hours. The solution was diluted with CH₂ Cl₂ and washed with water,brine, dried over anhydrous MgSO₄, and stripped. The residue wasdissolved in CH₂ Cl₂ and filtered to give 1.7 g of the title product; MS(FAB), 755 (m).

A solution of the above material (1.7 g) in CH₃ OH (15 mL) and citricacid (10%, 5 mL) was heated at reflux for 16 hours. The solution wasevaporated and the CH₃ OH solution was diluted with water and extractedwith hexane. The aqueous solution was finally extracted with EtOAc andthe extract was washed with water, dried over MgSO₄, stripped, and theresidue chromatographed (CH₂ Cl₂ /MeOH; 9:1) to give 0.8 g of the titlecompound; MS (FAB), 512 (m+1);

Analysis calculated for C₂₈ H₂₉ N₇ O₃.0.51 EtOAc.0.63 H₂ O; C, 63.55; H,6.11; N, 17.24. Found: C, 63.54; H, 5.81; N, 17.23.

We claim:
 1. A compound of formula ##STR9## or a pharmaceuticallyacceptable salt thereof wherein R₁ isadamantylmethyl, phenyl, biphenyl,or naphthyl, each of which is unsubstituted or substituted by one tothree substituents selected from the group consisting ofCl, Br, F, I,alkyl of from one to four carbon atoms, nitro tetrazol-5-yl, alkoxy offrom one to four carbon atoms, hydroxy, SO₃ H, SO₂ alkyl of from one tofour carbon atoms, CN, C_(n) F_(2n+1) wherein n is an integer of from 11 to 3, CO₂ R₄, SO₂ NHR₄, NHSO₂ R₄, NHSO₂ C_(n) F_(2n+1), COn(R₄)₂wherein R₄ is hydrogen or lower alkyl; X is a single bone, S, or O; R₂isalkyl of from two to ten carbon atoms, alkenyl of from two to tencarbon atoms, alkynyl of from three to ten carbon atoms, cycloalkyl offrom three to six carbon atoms, (CH₂)_(m) phenyl wherein m is an integerof from zero to eight and phenyl is unsubstituted or substituted by oneto three substituents selected from the groups consisting ofalkyl offrom one to four carbon atoms, nitro, Cl, Br, F, I, hydroxy, alkoxy offrom one to four carbon atoms, or NR₄ R₄ wherein R₄ is as defined above;R₃ ishydrogen, Cl, Br, F, I, CHO, hydroxymethyl, a straight or branchedalkyl of from 1-10 carbon atoms, aryl selected from the group consistingof phenyl, 1-naphthyl and, 2-naphthyl, CO₂ R₄, CONR₄ R₄, NO₂, or C_(n)F_(2n+1) wherein n is as defined above; R₄ is hydrogen or alkyl of fromone to five carbon atoms, R is hydrogen or alkyl of from one to fivecarbon atoms which alkyl is unsubstituted or substituted withCN, CO₂ R₄,tetrazol-5-yl, CONHR₄, CONH(CH₂)_(n) CO₂ R₄, phenyl unsubstituted orsubstituted by one to three substituents selected from alkyl of from oneto four carbon atoms, nitro, Cl, F, I, hydroxy, alkoxy of from one tofour carbon atoms, or NR₄ R₄ wherein R₄ is as defined above; or R isOR₄, or O(CH₂)_(n) CO₂ R₄ ; R₅ and R₆ are each independentlyhydrogen,halogen, alkyl of from one to five carbon atoms, alkoyloxy of from oneto five carbon atoms, NO₂, NCOR₄, NHSO₂ R₄, (CH₂)_(n) CO₂ R₄ wherein nand R₄ are as defined B' is a bond; the is a double or single bond; andthe indicates both E and Z isomer of the compound.
 2. A compoundaccording to claim 1 wherein:R₁ isphenyl biphenyl, or naphthyl, each ofwhich is unsubstituted or substituted by one to three substituentsselected from the group consisting ofCl, F, alkyl of from one to fourcarbon atoms, nitro, tetrazol-5-yl, alkoxy of from one to four carbonatoms, hydroxy, SO₃ H, CN, C_(n) F_(2n+1) wherein n is an integer offrom 1 to 3, CO₂ R₄, SO₂ NHR₄, NHSO₂ R₄, CONR₄ R₄ wherein R₄ is hydrogenor lower alkyl; X is a single bond or S; R₂ is alkyl of from two toeight carbon atoms, or cycloalkyl of from three to six carbon atoms; R₃ishydrogen, Cl, F, I, CHO, hydroxymethyl, alkyl, aryl, CO₂ R₄, CONR₄ R₄,NO₂, or C_(n) F_(2n+1) wherein n is as defined above; R₄ is hydrogen oralkyl of from one to four carbon atoms, R is hydrogen or alkyl of fromone to four carbon atoms unsubstituted or substituted withCO₂ R₄,tetrazol-5-yl, CONHR₄, CONHR₄ wherein R₄ is as defined above; R₅ and R₆are each independentlyhydrogen, alkyl of from one to four carbon atoms,alkyloxy of from one to four carbon atoms, NO₂, NHCOR₄, NHSO₂ R₄,(CH₂)_(n) CO₂ R₄ wherein n and R₄ are defined above, B' is a bond, andthe is a double or single bond.
 3. A compound according to claim 1wherein:R₁ is phenyl substituted by one to three substituents selectedfrom the group consisting ofCl, F, trifluoromethyl, nitro, methyl,methoxy, hydroxy, sulfonamido, carboxy, carboC₁ -C₄ alkoxy, carbamoyl,CN, or tetrazol-5-yl; X is a single bond; R₂ is alkyl of from two toeight carbon atoms; R₃ is hydrogen; R₄ is hydrogen; R is CH₂ CO₂ R₄wherein R₄ is hydrogen or lower alkyl; R₅ is alkyl of from one to fourcarbon atoms or alkoxy of from one to four carbon atoms; R₆ is hydrogen;B is a bond; and the is a double bond.
 4. A compound according to claim1 selected from the group consisting ofEthyl4-[[2-butyl-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]-benzoate.Methyl4-[[2-butyl-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]-3-chlorobenzoate;Methyl4-[[2-butyl-5-[(1,2-dihydro-5-methyl-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate;Ethyl4-[[2-butyl-4-chloro-5-[(1,2-dihydro-6-methyl-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate;Methyl4-[[2-propyl-5-[(1,2-dihydro-1-methyl-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate;Methyl4-[[2-butyl-5-[(1,2-dihydro-4-methyl-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate;Methyl4-[[2-butyl-5-[(1,2-dihydro-7-methyl-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate;Methyl4-[[2-butyl-5-[(5-chloro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate;Methyl4-[[2-butyl-5-[(1,2-dihydro-7-methoxy-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate;and Ethyl3-[[2-butyl-1-[[4-(methoxycarbonyl)phenyl]methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-5-carboxylate.5. A compound according to claim 1 selected from the group consistingofEthyl4-[[2-butyl-4-chloro-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate;Ethyl3-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-1-acetate;Methyl4-[[2-butyl-5-[1,2-dihydro-1-(methylaminocarbonyl)-2-oxo-3H-indol-3-ylidene]methyl]-1H-imidazol-1-yl]methylbenzoate; Methyl4-[[2-butyl-5-[1,2-dihydro-1-hydroxy-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate.6. A compound according to claim 1 selected from the group consistingof4-[[2-Butyl-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoicacid;(E)-4-[[2-Butyl-4-chloro-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)]-1H-imidazol-1-yl]methyl]benzoicacid;4-[[2-Butyl-5-[(1,2-dihydro-7-methoxy-2-oxo-3H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoicacid;3-[[2-Butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-1-aceticacid;3-[[2-Butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-5-carboxylicacid;4-[[2-Butyl-5-[(1,2-dihydro-5-methyl-2-oxo-3H-indol-3ylidene)methyl]-1H-imidazol-1-yl]methyl]benzoicacid; and Ethyl (Z) -(±)-2,3-dihydro-3-[[3-[[4-(methoxycarbonyl)phenyl]methyl]-2-propyl-3H-imidazol-4yl]methylene]-4methyl-2-oxo-α-propyl-1H-indole-1-acetate;3-[[2-butyl-3-[[4-(1H-tetrazol-5-yl)-phenyl]methyl]-3H-imidazol-4-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-1-aceticacid; Methyl(Z)-2,3-dihydro-3-[[3-[[4-(methoxycarbonyl)phenyl]methyl]-2-propyl-3H-imidazol-4-yl]methylene]-4-methyl-2-oxo-1H-indole-1-acetate;4-[[2-butyl-5-8(1-butyl-1,2-dihydro-2-oxo-3H-indol-3-ylidenyl)methyl]-1H-imidazol-1-yl]methyl]-3-chlorobenzoicacid;4-[[2-butyl-5-[[1,2-dihydro-7-methyl-2-oxo-3H-indol-3-ylidenyl)methyl]-1H-imidazol-1-yl]-methyl]benzoicacid;4-[[5-[(1,2-dihydro-2-oxo-1-propyl-3H-indol-3-ylidenyl)methyl]-2-propyl-1H-imidazol-1-yl]methyl]benzoicacid;(E)-4-[[5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidenyl)methyl]-2-propyl-4-(1H-pyrrol-1-yl)-1H-imidazol-1-yl]methyl]benzoicacid; Ethyl(Z)-3-[[2-butyl-3-[[4-(methoxycarbonyl)phenyl]methyl]-3H-imidazol-4-yl]methylene]-2,3-dihydro-7-methoxy-2-oxo-1H-indole-1-acetate;Methyl4-[[5-[(1,2-dihydro-1-methyl-2-oxo-3H-indol-3-ylidenyl)methyl]-2-propyl-1H-imidazol-1-yl]-methyl]benzoate;Methyl2,3-dihydro-3-[[4-(methoxycarbonyl)phenyl]methyl]-2-propyl-3H-imidazol-4-yl]methylene]-2-oxo-1H-indole-7-acetate;(E)-3-[[3-[(4-carboxyphenyl)methyl]-2-propyl-3H-imidazol-4-yl]methylene]-2,3-dihydro-2-oxo-1H-indole-1-aceticacid; Benzoic acid,4-[[2-butyl-5-[[1-[(4-chlorophenyl)methyl]-2,3-dihydro-2-oxo-1-H-indol-3-ylidene]methyl]-1H-imidazol-1yl]methyl]-,(E)-; 1H-Indole-1-propanoic acid,3-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-,(E)-; Benzoic acid,4-[[2-butyl-5-[[2,3-dihydro-2-oxo-1-[(1H-tetrazol-5-yl)methyl]-1H-indol-3-ylidene]methyl]-1H-imidazol-1-yl]methyl]-,methyl ester, (E)-; 1H-Indole-1-propanoic acid,3-[[2-butyl-1-[[4-methoxycarbonyl)phenyl]methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-,ethyl ester, (E)-; Benzoic acid,4-[[2-butyl-5-[[1-(cyanomethyl)-2,3-dihydro-2-oxo-1H-indol-3-ylidene]methyl]-1H-imidazol-1-yl]methyl]-,methyl ester, (E); Benzoic acid,4-[[2-butyl-5-[[1-[2-(dimethylamino)ethyl]-2,3-dihydro-2-oxo-1H-indol-3-ylidene]methyl]-1H-imidazol-1-yl]methyl]-,methyl ester, (E)-; 1H-Indole-1-acetic acid,3-[[2-butyl-1-[[4-(1H-tetrazol-5-yl)phenyl]methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2oxo-,methyl ester; Benzoic acid,4-[[5-[(2,3-dihydro-1-methyl-2-oxo-1H-indol-3-ylidene)methyl]-2-propyl-4-(1H-pyrrol-1-yl)-1H-imidazol-1-yl]methyl]-,methyl ester, (E)-; Benzoic acid,4-[[2-butyl-5-[(1-butyl-2,3-dihydro-2-oxo-1H-indol-3-ylidene)methyl]-1H-imidazol-1-yl]methyl]-,methyl ester; 1H-Indole-1-acetic acid,2,3-dihydro-3-[[1-[[4-(methoxycarbonyl)phenyl]methyl]-2-propyl-4-(1H-pyrrol-1yl)-1H-imidazol-5yl]methylene]-2-oxo-,methyl ester, (E); Benzoic acid,4-[[5-[[2,3-dihydro-1-(1-methylethyl)-2-oxo-1H-indol-3-ylidene]methyl]-2-propyl-1H-imidazol-1-yl]methyl]-,methyl ester, (Z)-; Benzoic acid,4-[[5-[(1-butyl-2,3-dihydro-2-oxo-1H-indol-3-ylidene)methyl]-2-propyl-4-(1H-pyrrol-1yl)-1H-imidazol-1-yl]methyl]-,methyl ester, (E)-; Benzoic acid,4-[[2-butyl-5-[[2,3-dihydro-1-(2-methoxy-2-oxoethoxy)-2-oxo-1H-indol-3-ylidene]methyl]-1H-imidazol-1-yl]methyl]-,methyl ester; 1H-Indole-1-acetic acid,3-[[2-butyl-1-[[4-(1H-tetrazol-5-yl)phenyl]methyl]-1H-imidazol-5-yl]methylene]-2,3-dihydro-2-oxo-,ethyl ester; Benzoic acid,4-[[5-[(2,3-dihydro-2-oxo-1H-indol-3-ylidene)methyl]-2-ethyl-4-methyl-1H-imidazol-1-yl]methyl]-(E)-;and Benzoic acid,4-[[2-butyl-5-[(2,3-dihydro-2-oxo-1H-indol-3-yl)methyl]-1H-imidazol-1yl]methyl]-,methyl ester.